Optically active α-aminooxyketone derivatives and process for production thereof

ABSTRACT

The corresponding α-aminooxy ketone is manufactured with a high yield and a high enantioselectivity. A manufacturing method for an optically active α-aminooxy ketone derivative expressed by formula (1), wherein a ketone expressed by formula (2) is caused to react with a nitroso compound expressed by formula (3) in the presence of a proline derivative expressed by formula (4). 
                         
In the formula, R 1  and R 2  respectively denote an alkyl, alkenyl or alkynyl group, and R 1  and R 2  may be linked to form a ring. R 3  denotes an aryl, heterocyclic, alkyl, alkenyl or alkynyl group. A denotes a hydrogen atom, alkoxy group, aryloxy group, acyloxy group or silyloxy group which may have a substituent.

RELATED APPLICATION

This application claims priority to and the benefit of Japanese PatentApplication No. 2003-300367 filed Aug. 25, 2003 and Japanese PatentApplication No. 2004-153944 filed May 24, 2004.

TECHNICAL FIELD

The present invention relates to an α-aminooxy ketone derivative whichcan be easily converted into an α-hydroxy ketone useful for medicines,agricultural chemicals, and the like, and a manufacturing method bywhich the α-aminooxy ketone derivative can be obtained in a high yieldwith a high enantioselectivity.

BACKGROUND ART

Conventionally, an α-hydroxy ketone has been synthesized by firstconverting a ketone into an enolate or an equivalent thereof once, andthen causing a diastereoselective reaction or an enantioselectivereaction (see non-patent literature 1).

As an example of such a method, the method which converts a ketone intoa lithium enolate, and causes optically active oxadilysine as anoxidizer to act thereon as an oxidizer (see patent literatures 2 to 8);the method which, as an asymmetric catalytic reaction, converts a ketoneinto an enol ether, and then carries out asymmetric dihydroxylationthereof (see non-patent literatures 9 to 10); and the technique whichfurther carries out asymmetric epoxidation thereof (non-patentliteratures 10 to 14), are known.

As described above, with these methods, it is necessary to first converta ketone into the corresponding enolate or an equivalent thereof, andthe catalytic asymmetric oxidation reaction has presented the problemthat substrates with which a high asymmetric yield can be achieved arelimited. Further, there has been another problem in that the asymmetriccatalytic reaction requires use of an environmentally harmful metallicsalt.

Recently, a method for synthesizing an α-aminooxy ketone by converting aketone into a tin enolate, and then carrying out an asymmetric catalyzedreaction using nitrosobenzene using a catalytic amount of an opticallyactive activating agent has been reported (non-patent literature 15).

The α-aminooxy ketone can be easily converted into an α-hydroxy ketone,thus this technique provides a part of a useful α-hydroxy ketonesynthesizing method.

However, although this method requires a smaller amount of opticallyactive catalyst, it has presented problems in that, for example, thereis the need to first convert a ketone into a tin enolate; the tincompound has toxicity; and that the asymmetric catalyst used must beprepared from BINAP and AgOTf.

Thus, no excellent method for manufacturing an optically activeα-hydroxy ketone directly from a ketone by an asymmetric catalyticreaction using an easily available asymmetric source as an activatingagent has been provided. In addition, no manufacturing method whichproceeds with high yield and asymmetric yield, meeting the requirementsfor practical use, has been available. In other words, no efficientmanufacturing method from a ketone to an optically active α-hydroxyketone has been provided.

Non-patent literature 1: Zhou et al. (Zhou, P.; Chen, B. C.; Davis, F.A. “Asymmetric Oxidation Reactions”, Katsuki, T., Ed.; Oxford UniversityPress: Oxford, 2001; p 128)

Non-patent literature 2: Davis et al. (Davis, F. A.; Chen, B. C. Chem.Rev. 1992, 92, 919)

Non-patent literature 3: Davis et al. (Davis, F. A.; Haque, M. S. J.Org. Chem. 1986, 51, 4083)

Non-patent literature 4: Chen et al. (Chen, B. C.; Weismiller, M. C.;Davis, F. A.; Boschelli, D.; Empfield, J. R.; Smith, A. B. Tetrahedron1991, 47, 173)

Non-patent literature 5: Davis et al. (Davis, F. A.; Kumar, A. J. Org.Chem. 1992, 57, 3337)

Non-patent literature 6: Davis et al. (Davis, F. A.; Weismiller, M. C.;Murphy, C. K.; Reddy, R. T.; Chen, B. C. J. Org. Chem. 1992, 57, 7274)

Non-patent literature 7: Davis et al. (Davis, F. A.; Kumar, A.; Reddy,R. T.; Rajarathnam, E.; Chen, B. C.; Wade, P. A.; Shah, S. W. J. Org.Chem. 1993, 58, 7591)

Non-patent literature 8: Davis et al. (Davis, F. A.; Clark, C.; Kumar,A.; Chen, B. C. J. Org. Chem. 1994, 59, 1184)

Non-patent literature 9: Hashiyama et al. (Hashiyama, T.; Morikawa, K.;Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463)

Non-patent literature 10: Hashiyama et al. (Hashiyama, T.; Morikawa, K.;Sharpless, K. B. J. Org. Chem. 1992, 57, 5067)

Non-patent literature 11: Fukuda et al. (Fukuda, T.; Katsuki, T.Tetrahedron Lett. 1996, 37, 4389)

Non-patent literature 12: Adam et al. (Adam, W.; Rainer, T. F.;Stegmann, V. R.; Saha-Moller, C. R. J. Am. Chem. Soc. 1998, 120, 708)

Non-patent literature 13: Zhu et al. (Zhu, Y.; Yu, Y.; Yu, H.; Shi, Y.Tetrahedron Lett. 1998, 39, 7819)

Non-patent literature 14: Adam et al. (Adam, W.; Fell, R. T.;Saha-Moller, C. R.; Zhao, C-G Tetrahedron: Asymmetry 1998, 9, 397)

Non-patent literature 15: Momiyama et al. (Momiyama, N.; Yamamoto, H. J.Am. Chem. Soc., 2003, 125, 6038)

DISCLOSURE OF INVENTION Problems to Be Solved by the Invention

Therefore, the purposes of the present invention are to provide a methodfor manufacturing, in a manner that is industrially advantageous, anoptically active α-aminooxy ketone that is free from the above-mentionedproblems and, in turn, to efficiently obtain an α-hydroxy ketone.

Means to Solve the Problems

In view of such circumstances, the present inventors have conductedintensive research, and have completed the present invention, findingthat, by causing a ketone expressed by formula (2) to react with anitroso compound expressed by formula (3) in the presence of proline ora specific proline derivative, an α-aminooxy ketone can be obtained in ahigh yield with a high enantioselectivity.

That is, the present invention provides:

<1> A manufacturing method for an optically active α-aminooxy ketonederivative expressed by formula (1), wherein a ketone expressed byformula (2) is caused to react with a nitroso compound expressed byformula (3) in the presence of proline or a proline derivative expressedby formula (4).

In formulae (1) to (4), R¹ and R² respectively denote an alkyl, alkenylor alkynyl group which may have a substituent, and R¹ and R² may belinked to form a ring. R³ denotes an aryl, heterocyclic, alkyl, alkenylor alkynyl group which may have a substituent. A denotes a hydrogenatom, alkoxy group, aryloxy group, acyloxy group or silyloxy group whichmay have a substituent.

<2> The manufacturing method of item <1>, wherein A in formula (4) is asilyloxy group which may have a substituent.

<3> A manufacturing method for an optically active α-aminooxy ketonederivative expressed by formula (1′), wherein a ketone expressed byformula (2) is caused to react with a nitroso compound expressed byformula (3) in the presence of proline or a proline derivative expressedby formula (4′).

In formulae (1) to (4), R¹ and R² respectively denote an alkyl, alkenylor alkynyl group which may have a substituent, and R¹ and R² may belinked to form a ring. R³ denotes an aryl, heterocyclic, alkyl, alkenylor alkynyl group which may have a substituent. A denotes a hydrogenatom, alkoxy group, aryloxy group, acyloxy group or silyloxy group whichmay have a substituent.

<4> The manufacturing method of item <3>, wherein A in formula (4′) is asilyloxy group which may have a substituent.

<5> An optically active α-aminooxy ketone derivative or an enantiomerthereof which is expressed by formula (1a).

In formula (1a), —X—Y-Z-denotes one selected from the following groups.

Effects of the Invention

According to the present invention, an α-aminooxy ketone can be obtainedin a high yield with a high enantioselectivity.

When the catalyst is proline, the proline has the feature of beinginexpensive. When the catalyst used is a proline derivative and, inparticular super proline as described below, the correspondingα-aminooxy ketone can be manufactured at a stroke simply in a shortperiod of time with a high yield and a high enantioselectivity, ascompared to proline.

Best Mode for Carrying Out the Invention

The manufacturing method for α-aminooxy ketones of the present inventionprovides a manufacturing method for an α-aminooxy ketone, wherein aketone expressed by formula (2) as given above is caused to react with anitroso compound expressed by formula (3) in the presence of proline ora proline derivative expressed by formula (4) or (4′).

First, the raw material compounds will be described.

<Ketones Expressed by Formula (2)>

In formula (2), the alkyl group denoted by R¹ and R² preferably has 1 to20 carbons, and particularly preferably has 1 to 5 carbons or so.Specific examples of the alkyl group include a methyl group, an ethylgroup, propyl group, an isopropyl group, a n-butyl group, a sec-butylgroup, a t-butyl group, a pentyl group, a hexyl group, a heptyl group, an-octyl group, a 2-ethylhexyl group, a t-octyl group, a nonyl group, adecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, apentadecyl group, a n-hexadecyl group, a 2-hexyldecyl group, aheptadecyl group, an octadecyl group, a nonadecyl group, an icosylgroup, and the like. The alkyl group may further have a substituent, andas such a substituent, the following aryl group, heterocyclic group, andthe like can be mentioned.

Herein, examples of the aryl group include phenyl and naphthyl groups,which may have a substituent, and the like.

In addition, examples of the heterocycle in the heterocyclic groupinclude piperidine, furan, thiophene, pyrrole, pyrazole, imidazole,triazole, oxazole, isooxazole, thiazole, isothiazole, dioxolane,pyridine, pyrimidine, pyrazine, triazine, dioxane, dithiane, morpholine,azepine, oxepine, thiepine, and the like.

The aryl group and the heterocyclic group may further have asubstituent, and as such a substituent, an alkyl group, an alkenylgroup, a nitro group, a halogen atom (for example, a fluorine atom, achlorine atom, a bromine atom, or an iodine atom), and the like can bementioned.

In formula (2), the alkenyl group denoted by R¹ and R² preferably has 2to 20 carbons, and particularly preferably has 2 to 5 carbons or so.Specific examples of the alkenyl group include a vinyl group, a propenylgroup, such as an allyl group, or the like, a butylyl group, a pentenylgroup, a hexenyl group, a heptenyl group, an octenyl group, a nonenylgroup, a decenyl group, an undecenyl group, a dodecenyl group, atridecenyl group, a tetradecenyl group, a pentadecenyl group, ahexadecenyl group, a heptadecenyl group, a octadecenyl group, anonadecenyl group, an icosenyl group, and the like. The alkenyl groupmay further have a substituent, and as such a substituent, theabove-mentioned aryl group, heterocyclic group, and the like can bementioned.

The alkynyl group preferably has 2 to 20 carbons, and particularlypreferably has 2 to 5 carbons.

In the ketone expressed by formula (2), R¹ and R² may be linked to forma ring. Examples of such a ring include cyclohexane, cyclopentane,cycloheptane, cyclooctane, cyclononane, tetrahydrofuran,tetrahydropyran, piperidine, pyrrolidine, thiacyclohexane, and the like.These rings may further have a substituent, and as such a substituent,the above-mentioned alkyl group, alkenyl group, alkynyl group, arylgroup, heterocyclic group, and the like can be mentioned.

Specific examples of the ketone expressed by formula (2) includecyclohexanone, cyclopentanone, dimethylcyclohexanone,1,4-cyclohexanedione, monoethyleneketal, tetrahydropyran-4-on,piperidinone, 3-pentanone, tetrahydrothiopyran-4-on,3,3-dimethylcyclohexanone, cys-3,5-dimethylcyclohexanone,3-methylcyclohexanone, 3-phenylcyclohexanone, 4-tert-butylcyclohexanone,4-(tert-butyldiphenylsiloxy)cyclohexanone, cycloheptanone, 2-butanone,1,5-dioxaspiro[5.5]undeca-9-on, 1,5-diaspiro[5.5]undeca-9-on,4,4-dimethoxycyclohexanone, 4,4-diethoxycyclohexanone, and the like.

<Nitroso Compounds Expressed by Formula (3)>

In formula (3), as the aryl group denoted by R³, phenyl and naphthylgroups, which may have a substituent, and the like can be mentioned, andthe aryl group is preferably a phenyl group.

Examples of the heterocycle of the heterocyclic group denoted by R³ informula (3) include piperidine, furan, thiophene, pyrrole, pyrazole,imidazole, triazole, oxazole, isooxazole, thiazole, isothiazole,dioxolane, pyridine, pyrimidine, pyrazine, triazine, dioxane, dithiane,morpholine, azepine, oxepine, thiepine, and the like.

The aryl group and the heterocyclic group may further have asubstituent, and as such a substituent, an alkyl group, an alkenylgroup, a nitro group, a halogen atom (for example, a fluorine atom, achlorine atom, a bromine atom, or an iodine atom), and the like can bementioned.

In formula (3), the alkyl group denoted by R³ preferably has 1 to 20carbons, and particularly preferably has 1 to 5 carbons or so. Specificexamples of the alkyl group include a methyl group, an ethyl group, apropyl group, an isopropyl group, a n-butyl group, a sec-butyl group, at-butyl group, a pentyl group, a hexyl group, a heptyl group, a n-octylgroup, a 2-ethylhexyl group, a t-octyl group, a nonyl group, a decylgroup, a dodecyl group, a tridecyl group, a tetradecyl group, apentadecyl group, a n-hexadecyl group, a 2-hexyldecyl group, aheptadecyl group, a octadecyl group, a nonadecyl group, an icosyl group,and the like. The alkyl group may further have a substituent, and assuch a substituent, the above-mentioned aryl group, heterocyclic group,and the like can be mentioned.

In formula (3), the alkenyl group denoted by R³ preferably has 2 to 20carbons, and particularly preferably has 2 to 5 carbons or so. Specificexamples of the alkenyl group include a vinyl group, propenyl group,such as an allyl group, or the like, a butylyl group, a pentenyl group,a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, adecenyl group, an undecenyl group, a dodecenyl group, a tridecenylgroup, a tetradecenyl group, a pentadecenyl group, a hexadecenyl group,a heptadecenyl group, an octadecenyl group, a nonadecenyl group, anicosenyl group, and the like. The alkenyl group may further have asubstituent, and as such a substituent, the above-mentioned aryl group,heterocyclic group, and the like can be mentioned.

The alkynyl group denoted by R³ preferably has 2 to 20 carbons, andparticularly preferably has 2 to 5 carbons.

The nitroso compound expressed by formula (3) is preferablynitrobenzene.

<Proline or Proline Derivatives Expressed by Formula (4) or (4′)>

In the present invention, as the asymmetric catalyst, proline or aproline derivative expressed by formula (4) or (4′) is used.

In formulae (4) and (4′), A denotes a hydrogen atom, alkoxy group,aryloxy group, acyloxy group or silyloxy group which may have a hydrogenatom. Herein, as the alkoxy group, those which have 1 to 5 carbons, forexample, a methoxy group, an ethoxy group, a propoxy group, a butoxygroup, a pentyloxy group, and the like can be mentioned. As the aryloxygroup, a phenyloxy group, a naphthyloxy group, and the like can bementioned. As the acyloxy group, an acetoxy group, a benzoyloxy group,and the like can be mentioned. As the substituent of the silyloxy group,an alkyl group, an aryl group, an alkenyl group, and the like can bementioned. Those in which A is a methoxy group are described in theliterature of Roda et al. (Roda, Aldo; Cerre, Carolina; Manetta, AnnaC.; Cainelli, Gianfranco; Ronchi, Achille Umani; Panunzio, Mauro.Journal of Medicinal Chemistry (1996), 39 (11), 2270-6.), and those inwhich A is a benzoyloxy group are described in the literature of Perniet al. (Perni, Robert B.; Britt, Shawn D.; Court, John C.; Courtney,Lawrence F.; Deininger, David D.; Farmer, Luc J.; Gates, Cynthia A.;Harbeson, Scott L.; Kim, Joseph L.; Landro, James A.; Levin, Rhonda B.;Luong, Yu-Ping; O'Malley, Ethan T.; Pitlik, Janos; Rao, B. Govinda;Schairer, Wayne C.; Thomson, John A.; Tung, Roger D.; Van Drie, John H.;Wei, Yunyi. Bioorganic & Medicinal Chemistry Letters (2003), 13 (22),4059-4063.).

A is preferably a tert-butyldimethylsilyloxy group or atriisopropylsilyloxy group, and particularly preferably atert-butyldimethylsilyloxy group (the proline which has this group maybe called “super proline”) is preferable. The super proline causes thereaction to be completed in a much short period of time with theasymmetric yield being extremely high, as compared to the proline, inwhich A is a hydrogen atom. The super proline is public known (H.Ohtake, Y Imada, S-I. Murahashi, Bull. Chem. Soc. Jpn. 1999, 72, 2737.).

<Reaction Conditions>

First, by dissolving a ketone expressed by formula (2) as given aboveand proline or a proline derivative (4) [because, with (4′), thereaction progresses in the same way, herein (4) also means (4′)] into anorganic solvent, a solution is prepared. Herein, the proline or prolinederivative (4) is preferably used in an amount of 0.01 to 1 equiv., andparticularly in an amount of 0.1 to 0.3 equiv, relative to a nitrosocompound (3). Herein, the organic solvent to be used is preferably apolar solvent, such as DMF, DMSO, CH₃NO₂, NMP (N-methyl-pyrrolydinone),CH₃CN, CHCl₃, CH₂Cl₂, or the like, but it is not limited to these.

The solution of the ketone and the proline or proline derivative (4) iscooled to −50 deg C. to 25 deg C., and preferably to −10 to 10 deg C.,and in the subsequent reaction, it is preferable to maintain thistemperature.

The ketone is preferably used in an amount of 1 to 5 equiv., andparticularly preferably in an amount of 2 to 3 equiv, relative to thenitroso compound.

Next, the nitroso compound expressed by formula (3) is dissolved intothe above-mentioned solvent, and the solution is gradually added intothe solution of the ketone and the proline or proline derivative (4).

The period of time for adding the nitroso compound solution into thesolution of the ketone and the proline or proline derivative (4) ispreferably 1 min to 24 hr, and particularly preferably 3 to 12 hr. Forthe above-mentioned super proline, the period of time is preferably 5min to 5 hr. Also thereafter, the above-mentioned temperature ismaintained while stirring 10 min to 1 hr, whereby an α-aminooxy ketoneis obtained.

In this reaction, using L-proline will provide the α-aminooxy ketonewith the (R) isomer being given as the major product, while usingD-proline will provide the α-aminooxy ketone with the (S) isomer as themajor product. Here is an example when L-proline is used.

TABLE 1 Yield, % ee, % R 1 2 1 2 t-Bu 32 32 >99 94 OSi-t-BuPh₂ 47 24 >9996

Among the α-aminooxy ketones obtained by the method of the presentinvention, the following compounds and the enantiomers thereof are novelcompounds, and these are useful as synthesized intermediate productswhich can be easily converted into α-hydroxy ketones useful formedicines, agricultural chemicals, and the like.

EXAMPLES

Hereinafter, the present invention will be described on the basis ofEXAMPLES, however, the present invention is not limited to theseEXAMPLES.

Example 1 (Table 2, No. 1)

Cyclohexanone (1.2 mmol) and L-proline (0.18 mmol) are dissolved into2.7 mL of a DMF solution, and the solution is cooled to 0 deg C. Intothis solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) isdropped over 5.5 hr. After completion of the dropping, the solution isstirred at the same temperature for 30 min. A phosphate buffer solutionis added to stop the reaction; organic matters are extracted with ethylacetate; the organic phase is washed with saline, and dried with Na₂SO₄.After removing the Na₂SO₄ by filtration, the solvent is distilled awayunder reduced pressure. The product is purified by column chromatographyto obtain the α-aminooxy ketone in 79% yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-cyclohexanone

¹H NMR (CDCl₃): δ 1.37-1.75 (3H, m), 1.82-1.95 (2H, m), 4.27 (2H, dd,J=11.6, 6.2 Hz), 6.82 (3H, t, J=8.1 Hz), 7.12 (2H, t, J=7.6 Hz), 7.71(1H, s); ¹³C NMR (CDCl₃): δ 23.6, 27.1, 32.3, 40.7, 86.1, 114.3, 114.8,128.9, 148.0, 209.7; IR (KBr): 3041, 2942, 2865, 1716, 1600, 1494, 1132,1099, 1072, 1027 cm⁻¹; HRMS(FAB): Calculated value [C₂₂H₁₅NO₂]:205.1103, observed value: 205.1080; [α]_(D) ²³ +119 (c=0.84, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=34.3min, minor enantiomer tr=28.1 min.

Example 2 (Table 2, No. 3)

1,4-cyclohexadione monoethyleneketal (1.2 mmol) and L-proline (0.06mmol) are dissolved into 2.7 mL of a DMF solution, and the solution iscooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) ofnitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion of thedropping, the solution is stirred at the same temperature for 30 min. Aphosphate buffer solution is added to stop the reaction; organic mattersare extracted with ethyl acetate; the organic phase is washed withsaline, and dried with Na₂SO₄. After removing the Na₂SO₄ by filtration,the solvent is distilled away under reduced pressure. The product ispurified by column chromatography to obtain the α-aminooxy ketone in 96%yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(R)-7-anilinooxy-1,4-dioxaspiro[4.5]decane-8-on

¹H NMR (CDCl₃): δ 1.88-2.04 (2H, m), 2.16 (1H, t, J=12.8 Hz), 2.36-2.46(2H, m) 2.62 (1H, dt, J=14.0, 6.8 Hz), 4.38-4.21 (4H, m), 4.60 (1H, dd,J=12.9, 6.5 Hz), 6.87 (2H, d, J=7.7 Hz), 6.90 (1H, t, J=7.2 Hz), 7.20(2H, t, J=7.2 Hz); ¹³C NMR (CDCl₃): δ 34.9, 36.0, 39.7, 64.8, 64.9,82.7, 107.6, 114.5, 122.2, 128.9, 148.0, 208.6; IR (neat): 2960, 2888,1728, 1602, 1494, 1305, 1122, 1052 cm⁻¹; [α]_(D) ¹⁸ +78.7 (c=1.2,CHCl₃); HRMS (FAB): Calculated value [C₁₄H₁₇NO₄]: 263.1158, observedvalue: 263.1172.

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn (hexane:2-propanol 10:1). 0.5 mL/min; major enantiomer tr=26.5min, minor enantiomer tr=29.1 min.

Example 3 (Table 2, No. 4)

4,4-dimethylcyclohexanone (1.2 mmol) and L-proline (0.06 mmol) aredissolved into 2.7 mL of a DMF solution, and the solution is cooled to 0deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene(0.6 mmol) is dropped over 12 hr. After completion of the dropping, thesolution is stirred at the same temperature for 30 min. A phosphatebuffer solution is added to stop the reaction; organic matters areextracted with ethyl acetate; the organic phase is washed with saline,and dried with Na₂SO₄. After removing the Na₂SO₄ by filtration, thesolvent is distilled away under reduced pressure. The product ispurified by column chromatography to obtain the α-aminooxy ketone in 87%yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-4,4-dimethylcyclohexanone

¹H NMR (CDCl₃): δ 0.97 (s, 3H), 1.14 (s, 3H), 1.48-1.59 (3H, m), 4.38(1H, ddd, J=12.7, 6.4, 3.2 Hz), 2.21-2.28 (1H, m), 2.40 (1H, dt, J=14.1,6.5 Hz), 4.38 (1H, dd, J=12.9, 6.4 Hz), 6.79 (2H, d, J=7.8 Hz), 6, 81(1H, t, J=8.1 Hz), 7.13 (2H, t, J=8.1 Hz); ¹³C NMR (CDCl₃): δ 24.9,31.3, 31.9, 44.4, 83.2, 114.2, 121.9, 128.8, 148.1, 210.3; IR (KBr):3041, 2956, 2927, 1725, 1602, 1495, 1470, 1076, 740, 692 cm⁻¹; [α]_(D)¹⁹ +85.7 (c=0.33, CHCl₃); HRMS (FAB): Calculated value [C₁₄H₁₉NO₂]:233.1416, observed value: 233.1423.

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=9.1min, minor enantiomer tr=12.2 min.

Example 4 (Table 2, No. 5)

Tetrahydro-4H-pyran-4-on (1.2 mmol) and L-proline (0.06 mmol) aredissolved into 2.7 mL of a DMF solution, and the solution is cooled to 0deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene(0.6 mmol) is dropped over 12 hr. After completion of the dropping, thesolution is stirred at the same temperature for 30 min. A phosphatebuffer solution is added to stop the reaction; organic matters areextracted with ethyl acetate; the organic phase is washed with saline,and dried with Na₂SO₄. After removing the Na₂SO₄ by filtration, thesolvent is distilled away under reduced pressure. The product ispurified by column chromatography to obtain the α-aminooxy ketone in 55%yield with 96% ee.

The optical purity was determined by HPLC using a chiral column.

(R)-3-anilinooxy-tetrahydropyran-4-on

¹H NMR (CDCl₃): δ 2.53 (1H, dt, J=14.3, 2.9 Hz), 2.59-2.68 (1H, m),3.60-3.72 (1H, m), 4.09-4.17 (1H, m), 4.35-4.39 (1H, m), 4.42-4.46 (1H,m), 6.86 (2H, d, J=7.7 Hz), 6.91 (1H, t, J=7.4 Hz), 7.20 (2H, t, J=7.6Hz), 768 (1H, s); ¹³C NMR (CDCl₃): δ 42.3, 68.1, 70.1, 83.5, 114.8,122.6, 128.9, 147.7, 205.1; IR (KBr): 2969, 2923, 2861, 2364, 1724,1600, 1494, 1205, 1107, 694 cm⁻¹; [α]_(D) ²⁰ +47.5 (c=0.13, CHCl₃); HRMS(FAB): Calculated value [C₁₁H₁₃NO₃]: 207.0895, observed value: 207.0925.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=18.6min, minor enantiomer tr=23.7 min.

Example 5 (Table 2, No. 6)

1-methyl-4-piperidinone (1.2 mmol) and L-proline (0.06 mmol) aredissolved into 2.7 mL of a nitromethane solution, and the solution iscooled to 0 deg C. Into this solution, a nitromethane solution (0.9 mL)of nitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion ofthe dropping, the solution is stirred at the same temperature for 30min. A phosphate buffer solution is added to stop the reaction; organicmatters are extracted with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain the α-aminooxyketone in 45% yield with 99% ee.

The optical purity was determined by HPLC using a chiral column.

(R)-3-anilinooxy-1-methylpiperidine-4-on

¹H NMR (CDCl₃): δ 2.36-2.41 (2H, m), 2.38 (3H, s), 2.54-2.64 (1H, m),2.91-3.00 (1H, m), 3.31 (1H, dddd, J=6.4, 2.4, 2.4, 2.4 Hz), 4.49 (1H,dd, J=10.5, 6.4 Hz), 6.85-6.91 (3H, m), 7.17-7.21 (2H, m), 7.69 (1H, s);¹³C NMR (CDCl₃): δ 40.5, 45.6, 55.8, 59.4, 83.6, 115.0, 122.8, 129.3,148.3, 207.6 IR (neat): 2948, 2852, 2798, 1727, 1600, 1494, 1143, 1060,904, 779, 754, 694 cm⁻¹; HRMS (FAB): Calculated value [C₁₂H₁₆N₂O₂]:220.1211, observed value: 220.1248.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=14.2min, minor enantiomer tr=17.4 min.

Example 6 (Table 1, No. 1)

4-tert-butylcyclohexanone (2.2 mmol) and L-proline (0.18 mmol) aredissolved into 8.1 mL of a DMF solution, and the solution is cooled to 0deg C. Into this solution, a DMF solution (2.7 mL) of nitrosobenzene(1.80 mmol) is dropped over 20 hr. After completion of the dropping, thesolution is stirred at the same temperature for 30 min. A phosphatebuffer solution is added to stop the reaction; organic matters areextracted with ethyl acetate; the organic phase is washed with saline,and dried with Na₂SO₄. After removing the Na₂SO₄ by filtration, thesolvent is distilled away under reduced pressure. The product ispurified by column chromatography to obtain the (2R,4R)-α-aminooxyketone and the (2R,4S)-α-aminooxy ketone as a mixture. Yield is 64%;from the analysis by NMR, the respective yields of the (2R,4R)- and(2R,4S)-isomers being 32% and 32%. By taking a part, and repeating thethin-layer chromatography a few times, the (2R,4R)- and (2R,4S)-isomerswere separated from each other.

The optical purity was determined by HPLC using a chiral column.

(2R,4R)-2-anilinooxy-4-tert-butylcyclohexanone

¹H NMR (CDCl₃): δ 0.83 (9H, s), 1.31 (1H, dddd, J=13.4, 4.2, 4.2, 4.2Hz), 1.45-1.62 (2H, m), 1.93-2.02 (1H, m), 2.24 (1H, dd, J=13.7, 5.9Hz), 2.30-2.38 (2H, m), 4.30 (1H, dd, J=12.5, 6.0 Hz), 6.78-6.85 (3H,m), 7.13 (2H, t, J=8.2 Hz), 7.76 (1H, s); ¹³C NMR (CDCl₃): δ 27.6, 32.5,33.6, 39.7, 45.9, 85.8, 114.5, 122.0, 128.9, 148.1, 210.2; IR (neat):2960, 2869, 1728, 1602, 1494, 1367, 1097, 742, 692 cm⁻¹; [α]_(D) ¹⁹−11.8 (c=0.87, CHCl₃); HRMS (FAB): Calculated value [C₁₆H₂₃NO₂]:261.1729, observed value: 261.1729.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=10.2min, minor enantiomer tr=11.0 min.

(2R,4S)-2-anilinooxy-4-tert-butylcyclohexanone

¹H NMR (CDCl₃): δ 0.80 (9H, s), 1.40 (1H, dddd, J=13.4, 4.2, 4.2, 4.2Hz), 1.56-1.65 (1H, m), 1.75 (1H, tt, J=12.2, 3.5 Hz), 1.93-2.01 (1H,m), 2.16-2.18 (2H, m), 2.63 (1H, dt, J=13.9, 6.0 Hz), 4.11 (1H, t, J=4.4Hz), 6.82 (2H, d, J=8.2 Hz), 6.85 (1H, t, J=7.3 Hz), 7.06 (1H, s),7.15-7.18 (2H, m); ¹³C NMR (CDCl₃): δ 27.3, 32.2, 32.3, 38.0, 41.3,84.7, 114.9, 122.6, 128.8, 147.8, 211.6; IR (neat): 2960, 2869, 1724,1673, 1602, 1494, 1367, 1083, 748 cm⁻¹; [α]_(D) ²³ −53.0 (c=0.62,CHCl₃); HRMS (FAB): Calculated value [C₁₆H₂₃NO₂]: 261.1729, observedvalue: 261.1720.

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn(hexane:2-propanol 100:1). 1.0 mL/min; major enantiomer tr=11.1min, minor enantiomer tr=12.5 min.

Example 7 (Table 1, No. 2)

4-tert-butyldiphenylsilyloxycyclohexanone (2.2 mmol) and L-proline (0.18mmol) are dissolved into 8.1 mL of a DMF solution, and the solution iscooled to 0 deg C. Into this solution, a DMF solution (2.7 mL) ofnitrosobenzene (1.80 mmol) is dropped over 20 hr. After completion ofthe dropping, the solution is stirred at the same temperature for 30min. A phosphate buffer solution is added to stop the reaction; organicmatters are extracted with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain the(2R,4R)-α-aminooxy ketone and the (2R,4S)-α-aminooxy ketone as amixture. Yield is 71%; from the analysis by NMR, the respective yieldsof the (2R,4R)- and (2R,4S)-isomers being 47% and 24%. By taking a part,and repeating the thin-layer chromatography a few times, the (2R,4R)-and (2R,4S)-isomers were separated from each other.

The optical purity was determined by HPLC using a chiral column.

(2R,4R)-2-anilinooxy-4-(tert-butyldiphenylsiloxy)cyclohexanone

¹H NMR (CDCl₃): δ 0.98 (9H, s), 1.58 (1H, t, J=12.7 Hz), 1.70 (1H,J=12.9 Hz), 1.87-1.96 (1H, m), 2.22-2.32 (2H, m), 2.84 (1H, dt, Jd=6.0,Jt=13.8 Hz), 4.23 (1H, brs), 4.81 (1H, dd, J=12.6, 6.2 Hz), 6.76 (2H, d,J=8.2 Hz), 6.83 (1H, t, J=6.9 Hz), 7.13 (2H, t, J=6.9 Hz), 7.32 (6H, m),7.57 (4H, dd, J=15.4, 7.8 Hz), 7.69 (1H, s); ¹³C NMR (CDCl₃): δ 19.2,27.0, 34.1, 35.7, 39.2, 67.5, 82.4, 114.5, 122.1, 127.8, 128.9, 130.0,133.5, 135.6, 148.1, 209.9; IR (neat): 2956, 2931, 1725, 1602, 1494,1427, 1112, 1076, 821, 701 cm⁻¹; [α]_(D) ¹⁸ +18.2 (c=0.231, CHCl₃); HRMS(FAB): Calculated value [C₂₈H₃₃NO₃Si]: 459.2230, observed value:459.2273.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=6.6min, minor enantiomer tr=7.3 min.

(2R,4R)-2-anilinooxy-4-(tert-butyldiphenylsiloxy)cyclohexanone

¹H NMR (CDCl₃): δ 1.08 (9H, s), 1.87-1.95 (1H, m), 2.00 (1H, dt, J=12.5,10.7 Hz), 2.04-2.18 (2H, m), 2.28-2.36 (1H, m), 2.42-2.48 (1H, m),4.09-4.18 (2H, m), 6.81 (2H, d, J=7.9 Hz), 6.93 (1H, t, J=7.9 Hz), 7.22(2H, t, J=7.9 Hz), 7.39-7.46 (6H, m), 7.65-7.70 (4H, m), 7.53 (1H, brs);[α]_(D) ¹⁹ +57.8 (c=1.18, CHCl₃); HRMS (FAB): Calculated value[C₂₈H₃₃NO₃Si]: 459.2230, observed value: 459.2263.

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=10.3min, minor enantiomer tr=11.3 min.

Example 8 (Table 3, Entry 1, Catalyst 10 mol %, Temperature −20 deg C.)

Into a CH₃CN solution (3.0 mL) of proline (0.06 mmol), propanal (1.8mmol) and nitrosobenzene (0.6 mmol) are added at −20 deg C., and thesolution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL)and NaBH₄ (3 mmol) are added, and the solution is stirred for 10 min;then a phosphate buffer solution is added to stop the reaction; organicmatters are extracted with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to quantitatively obtainthe β-aminoalcohol with 99% ee.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-propanol

¹H NMR (CDCl₃): δ 1.24 (3H, d, J=6.4 Hz), 2.34 (1H, brs), 3.72 (1H, dd,=12.0, 6.6 Hz), 3.80 (1H, dd, J=12.0, 2.9 Hz), 4.09-4.13 (1H, m),6.94-6.99 (3H, m), 7.23-7.28 (2H, m); ¹³C NMR (CDCl₃): δ 15.3, 65.9,80.0, 114.4, 122.0, 128.9, 148.5; IR (KBr): 3270, 2929, 1600, 1492,1062, 761, 669 cm⁻¹; [α]_(D) ²¹ +1.8 (c=0.57, CHCl₃), 98% ee; HRMS(FAB): Calculated value [C₉H₁₃NO₂]: 167.0946, observed value: 167.0908.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=10.3min, minor enantiomer tr=9.3 min.

Example 9 (Table 3, Entry 2, Catalyst 10 mol %, Temperature −20 deg C.)

Into a CH₃CN solution (3.0 mL) of proline (0.06 mmol), butanal (1.8mmol) and nitrosobenzene (0.6 mmol) are added at −20 deg C., and thesolution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL)and NaBH₄ (3 mmol) are added, and the solution is stirred for 10 min;then a phosphate buffer solution is added to stop the reaction; organicmatters are extracted with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain theβ-aminoalcohol in 88% yield with 98% ee.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-butanol

¹H NMR (CDCl₃): δ 0.98 (3H, t, J=7.5 Hz), 1.51-1.58 (1H, m), 1.65-1.70(1H, m), 3.70-3.74 (1H, m), 3.78-3.87 (2H, m), 6.92-6.96 (3H, m), 7.23(2H, t, J=7.6 Hz); ¹³C NMR (CDCl₃): δ 10.1, 22.9, 64.8, 85.2, 114.8,122, 4, 128.9, 148.4; IR (KBr): 3409, 3274, 2879, 1602, 1457, 1122,1052, 896, 767 cm⁻¹; [α]_(D) ¹⁶ +24.6 (c=0.74, CHCl₃), 99% ee; HRMS(FAB): Calculated value [C₁₀H₁₅NO₂]: 181.1103, observed value: 181.1128.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=11.0min, minor enantiomer tr=9.9 min.

Example 10 (Table 3, Entry 3, Catalyst 30 mol %, Temperature −20 deg C.)

Into a CH₃CN solution (3.0 mL) of proline (0.18 mmol), pentanal (1.8mmol) and nitrosobenzene (0.6 mmol) are added at −20 deg C., and thesolution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL)and NaBH4 (3 mmol) are added, and the solution is stirred for 10 min;then a phosphate buffer solution is added to stop the reaction; organicmatters are extracted with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain theβ-aminoalcohol in 81% yield with 98% ee.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-pentanol

¹H NMR (CDCl₃): δ 0.91 (3H, m), 1.3-1.49 (3H, m), 1.58-1.67 (1H, m),3.69 (1H, dd, J=12.0, 6.3 Hz), 3.80 (1H, dd, J=12.0, 2.6 Hz), 3.87-3.92(1H, m), 6.90-6.96 (3H, m), 7.19-7.23 (2H, m); ¹³C NMR (CDCl₃): δ 14.1,18.9, 32.0, 65.0, 83.7, 114.7, 122.3, 128.9, 148.4; IR (KBr): 3400,3282, 2958, 2933, 2873, 1602, 1494, 1465, 1124, 1027, 896, 775 cm⁻¹;[α]_(D) ¹⁶ +24.2 (c=0.34, CHCl₃), 98% ee; HRMS (FAB): Calculated value[C₁₁H₁₇NO₂]: 195.1259, observed value: 195.1247.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=10.3min, minor enantiomer tr=9.3 min.

Example 11 (Table 3, Entry 4, Catalyst 30 mol %, Temperature 0 deg C.)

Into a CH₃CN solution (3.0 mL) of proline (0.18 mmol), 3-methyl-butanal(1.8 mmol) and nitrosobenzene (0.6 mmol) are added at 0 deg C., and thesolution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL)and NaBH₄ (3 mmol) are added, and the solution is stirred for 10 min;then a phosphate buffer solution is added to stop the reaction; organicmatters are extracted with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain theβ-aminoalcohol in 77% yield with 97% ee.

The optical purity was determined by HPLC using a chiral column.

(R)-3-methyl-2-anilinooxy-butanol

¹H NMR (CDCl₃): δ 0.99 (3H, d, J=6.9 Hz), 1.03 (3H, d, J=6.9 Hz),1.99-2.04 (1H, m), 3.70-3.74 (1H, m), 3.81-3.86 (2H, m), 6.95-7.01 (3H,m), 7.23-7.28 (2H, m); ¹³C NMR (CDCl₃): δ 19.0, 19.2, 29.2, 64.2, 89.0,115.5, 123.0, 129.4, 148.7; IR (KBr): 3397, 3272, 2962, 2933, 2875,1602, 1494, 1469, 1051, 1025, 898, 742, 692 cm⁻¹; [α]_(D) ¹⁶ +35.8(c=0.42, CHCl₃), 99% ee; HRMS (FAB): Calculated value [C₁₁H₁₇NO₂]:195.1259, observed value: 195.1280.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=9.4min, minor enantiomer tr=8.4 min.

Example 12 (Table 3, Entry 5, Catalyst 30 mol %, Temperature 0 deg C.)

Into a CH₃CN solution (3.0 mL) of proline (0.18 mmol), 3-phenyl-propanal(1.8 mmol) and nitrosobenzene (0.6 mmol) are added at 0 deg C., and thesolution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL)and NaBH₄ (3 mmol) are added, and the solution is stirred for 10 min;then a phosphate buffer solution is added to stop the reaction; organicmatters are extracted with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain theβ-aminoalcohol in 72% yield with 99% ee.

The optical purity was determined by HPLC using a chiral column.

(R)-3-phenyl-2-anilinooxy-propanol

¹H NMR (CDCl₃): δ 2.25 (1H, brs), 2.77 (1H, dd, J=13.7, 6.9 Hz), 2.95(1H, dd, J=13.7, 6.9 Hz), 3.65 (1H, dd, J=11.8, 5.8 Hz), 3.77 (1H, d,J=11.8 Hz), 4.06 (1H, m), 6.76 (1H, d, J=8.0 Hz), 6.86 (1H, t, J=8.0Hz), 6.94 (1H, brs), 7.10-7.23 (7H, m); ¹³C NMR (CDCl₃): δ 36.5, 64.2,85.0, 114.8, 122.5, 126.5, 128.5, 128.9, 129.4, 137.8, 148.3; IR (KBr):3390, 3280, 1600, 1494, 1454, 1240, 1083, 1070, 1029, 898, 767, 744, 694cm⁻¹; [α]_(D) ¹⁶ +63.3 (c=0.71, CHCl₃), 99% ee; HRMS (FAB): Calculatedvalue [C₁₅H₁₇NO₂]: 243.1259, observed value: 243.1228.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=16.4min, minor enantiomer tr=13.6 min.

Example 13 (Table 3, Entry 6, Catalyst 30 mol %, Temperature −20 deg C.)

Into a CH₃CN solution (3.0 mL) of proline (0.18 mmol), phenylacetaldehyde (1.8 mmol) and nitrosobenzene (0.6 mmol) are added at −20deg C., and the solution is stirred for 24 hr at the same temperature.i-PrOH (1.0 mL) and NaBH₄ (3 mmol) are added, and the solution isstirred for 10 min; then a phosphate buffer solution is added to stopthe reaction; organic matters are extracted with ethyl acetate; theorganic phase is washed with saline, and dried with Na₂SO₄. Afterremoving the Na₂SO₄ by filtration, the solvent is distilled away underreduced pressure. The product is purified by column chromatography toobtain β-aminoalcohol in 62% yield with 99% ee.

The optical purity was determined by HPLC using a chiral column.

(R)-2-phenyl-2-anilinooxy-ethanol

¹H NMR (CDCl₃): δ 2.52 (1H, brs), 3.77 (1H, dd, J=12.2, 3.3 Hz), 3.93(1H, dd, J=12.2, 8.1 Hz), 4.97 (1H, dd, J=8.1, 3.3 Hz), 6.92-6.95 (4H,m), 7.20-7.24 (2H, m), 7.31-7.38 (5H, m); ¹³C NMR (CDCl₃): δ 63.3, 86.5,115.0, 122.5, 127.1, 128.4, 128.7, 129.0, 137.8, 147.9; IR (KBr): 3272,3031, 2921, 1600, 1494, 1454, 1309, 1072, 1027, 896, 759 cm⁻¹; [α]_(D)¹⁷ −126.5 (c=0.52, CHCl₃), 99% ee; HRMS (FAB): Calculated value[C₁₄H₁₅NO₂]: 229.1103, observed value: 229.1111.

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=10.5min, minor enantiomer tr=11.6 min.

Examples in Table 4 Example 14 (Table 4, Entry 1)

Into a DMF solution (2.7 mL) of 3,3-dimethylcyclohexanone (1.2 mmol) andproline (0.06 mmol), a DMF solution (0.9 mL) of nitrosobenzene (0.6mmol) is added at 0 deg C. over 38 hr, and the solution is stirred for0.5 hr at the same temperature. A phosphate buffer solution is added tostop the reaction; organic matters are extracted three times with ethylacetate; the organic phase is washed with saline, and dried with Na₂SO₄.After removing the Na₂SO₄ by filtration, the solvent is distilled awayunder reduced pressure. The product is purified by column chromatographyto obtain the α-aminooxy ketone in 43% yield with 99% ee. Diastereomerratio is 88:12.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-5,5-dimethylcyclohexanone

¹H NMR (CDCl₃): δ 0.92 (3H, s), 1.06 (3H, s), 1.63-167 (1H, m),1.63-1.96 (2H, m), 1.96 (1H, dq, J=12.7, 4.8 Hz), 2.21 (1H, dt, J=13.1,2.5 Hz), 2.25-2.31 (2H, m), 4.33 (1H, dd, J=12.1, 7.1 Hz), 6.89-6.94(3H, m), 7.21-7.25 (2H, m), 7.77 (1H, brs); ¹³C NMR (CDCl₃): δ 25.4,27.8, 31.2, 36.6, 36.8, 53.5, 85.6, 114.5, 122.1, 128.9, 148.1, 209.5;IR (KBr): 2960, 2923, 1718, 1602, 1496, 1103, 1079, 794, 757, 692 cm⁻¹;HRMS (FAB): Calculated value [C₁₄H₁₉NO₂]: 233.1473, observed value:233.1395; [α]_(D) ²⁴ +132.1 (c=0.43, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=17.7min, minor enantiomer tr=14.6 min.

Example 15 (Table 4, Entry 2)

Into a DMF solution (2.7 mL) of cys-3,5-dimethylcyclohexanone (1.2 mmol)and proline (0.06 mmol), a DMF solution (0.9 mL) of nitrosobenzene (0.6mmol) is added at 0 deg C. over 26 hr, and the solution is stirred for0.5 hr at the same temperature. A phosphate buffer solution is added tostop the reaction; organic matters are extracted three times with ethylacetate; the organic phase is washed with saline, and dried with Na₂SO₄.After removing the Na₂SO₄ by filtration, the solvent is distilled awayunder reduced pressure. The product is purified by column chromatographyto obtain the α-aminooxy ketone in 60% yield with 99% ee. Diastereomerratio is 70:30.

The optical purity was determined by HPLC using a chiral column.

(2R,3R,5S)-2-anilinooxy-3,5-dimethylcyclohexanone

¹H NMR (CDCl₃): δ 1.04 (3H, d, J=6.5 Hz), 1.21 (3H, d, J=7.0 Hz),1.53-1.59 (2H, m), 1.77-1.96 (2H, m), 2.22 (1H, dd, J=12.5, 3.9 Hz),2.52 (1H, t, J=12.5 Hz), 3.98 (1H, d, J=1.2 Hz), 6.90-6.98 (3H, m),7.22-7.26 (2H, m); ¹³C NMR (CDCl₃): δ 17.6, 19.1, 22.3, 34.3, 37.6,38.5, 45.5, 89.8, 114.9, 122.6, 128.9, 147.9, 211.4; IR (KBr): 3268,2960, 2927, 1716, 1494, 1455, 1284, 769, 738, 692 cm⁻¹; HRMS (FAB):Calculated value [C₁₄H₁₉NO₂]: 233.1416, observed value: 233.1431;[α]_(D) ²⁴ +48.1 (c=0.57, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=10.7min, minor enantiomer tr=9.8 min.

The absolute configuration was determined by converting a diol obtainedby causing NaBH₄ to act on 13a into(1S,2R,3R,5S)-1,2-bis(p-bromobenzoyloxy)-3,5-dimethylcyclohexane, andapplying the CD-chirality method thereto.

(2R,3S,5R)-2-anilinooxy-3,5-dimethylcyclohexanone

¹H NMR (CDCl₃): δ 1.02 (3H, d, J=6.2 Hz), 1.29 (3H, d, J=6.3 Hz),1.86-2.02 (4H, m), 2.09 (1H, t, J=13.0 Hz), 2.38-2.42 (1H, m), 4.05 (1H,d, J=11.4 Hz), 6.90-6.94 (3H, m), 7.21-7.25 (2H, m), 7.95 (1H, brs); ¹³CNMR (CDCl₃): δ 19.5, 22.0, 33.5, 37.8, 41.8, 48.6, 91.2, 114.6, 122.0,128.9, 148.2, 209.4; IR (KBr): 3307, 2954, 1720, 1602, 1496, 1097, 887,761, 738, 694, 582, 501 cm⁻¹; HRMS (FAB): Calculated value [C₁₄H₁₉NO₂]:233.2416, observed value: 233.1400; [α]_(D) ²⁴ +183.6 (c=0.36, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=31.1min, minor enantiomer tr=15.3 min.

The absolute configuration was determined by converting a diol obtainedby causing NaBH₄ to act on 13b into(1S,2R,3S,5R)-1,2-bis(p-bromobenzoyloxy)-3,5-dimethylcyclohexane, andapplying the CD-chirality method thereto.

Example 16 (Table 4, Entry 4)

Into a DMF solution (2.7 mL) of 3-phenylcyclohexanone (1.2 mmol) andproline (0.06 mmol), a DMF solution (0.9 mL) of nitrosobenzene (0.6mmol) is added at 0 deg C. over 29 hr, and the solution is stirred for0.5 hr at the same temperature. A phosphate buffer solution is added tostop the reaction; organic matters are three times extracted with ethylacetate; the organic phase is washed with saline, and dried with Na₂SO₄.After removing the Na₂SO₄ by filtration, the solvent is distilled awayunder reduced pressure. The product is purified by column chromatographyto obtain the α-aminooxy ketone in 72% yield with 99% ee for the majorproduct. Diastereomer ratio is 32:32:32:4.

The optical purity was determined by HPLC using a chiral column.

(2R,5R)-2-anilinooxy-5-phenylcyclohexanone

¹H NMR (CDCl₃): δ 1.85-2.03 (2H, m), 2.14-2.18 (1H, m), 2.50-2.57 (1H,m), 2.60-2.69 (2H, m), 2.96-3.04 (1H, m), 4.52 (1H, dd, J=11.9, 6.2 Hz);¹³C NMR (CDCl₃): δ 31.2, 31.7, 45.3, 48.0, 85.9, 114.5, 122.2, 126.4,127.0, 128.8, 128.9, 143.3, 148.1, 208.4; IR(KBr): 3278, 2952, 1718,1604, 1494, 1415, 1029, 794, 748, 694 cm⁻¹; HRMS (FAB): Calculated value[C₁₈H₁₉NO₂]: 281.1416, observed value: 281.1396; [α]_(D) ²³ +91.6(c=0.41, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Icolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=22.4min, minor enantiomer tr=18.4 min.

Example 17 (Table 5, Entry 5)

Into a DMF solution (2.7 mL) of 3-(4-tert-butylphenylthio)cyclohexanone(1.2 mmol) and proline (0.06 mmol), a DMF solution (0.9 mL) ofnitrosobenzene (0.6 mmol) is added at 0 deg C. over 13 hr, and thesolution is stirred for 0.5 hr at the same temperature. A phosphatebuffer solution is added to stop the reaction; organic matters areextracted three times with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain the α-aminooxyketone in 61% yield with 99% ee for the major product. Diastereomerratio is 46:21:33.

The optical purity was determined by HPLC using a chiral column.

(2R,5S)-2-anilinooxy-5-(4-tert-butylphenylthio)cyclohexanone

¹H NMR (CDCl₃): δ 1.28 (9H, s), 1.55-1.65 (1H, m), 1.72-1.86 (1H, m),1.94-2.05 (1H, m), 2.18-2.37 (2H, m), 2.43-2.52 (1H, m), 3.35 (1H, dddd,J=11.5, 11.5, 4.3, 4.3 Hz), 4.26 (1H, d, J=11.2 Hz), 6.94 (1H, t, J=7.1Hz), 7.17 (2H, d, J=7.7 Hz), 7.21-7.28 (2H, m), 7.30 (2H, d, J=8.4 Hz),7.44 (2H, d, J=8.4 Hz); ¹³C NMR (CDCl₃): δ 24.6, 31.2, 32.1, 34.6, 40.3,51.0, 88.6, 114.9, 122.2, 126.1, 126.3, 128.9, 134.2, 135.1, 148.1,151.5, 207.4; IR (KBr): 2960, 1727, 1600, 1494, 1120, 1014, 904, 829,740, 694 cm⁻¹; HRMS (FAB): Calculated value [C₂₂H₂₇NO₂S]: 369.1763,observed value: 369.1769; [α]_(D) ²³ +56.5 (c=0.27, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=15.0min, minor enantiomer tr=13.9 min.

(2R,5R)-2-anilinooxy-5-(4-tert-butylphenylthio)cyclohexanone

¹H NMR (CDCl₃): δ 1.30 (9H, s), 1.73-1.90 (2H, m), 2.23-2.35 (1H, m),2.35-2.50 (2H, m), 2.71-2.82 (2H, m), 3.15-3.28 (1H, m), 4.37 (1H, dd,J=11.3, 6.2 Hz), 6.85-6.96 (3H, m), 7.18-7.27 (2H, m), 7.30-7.38 (4H,m), 7.74 (1H, brs); ¹³C NMR (CDCl₃): δ 30.1, 30.7, 31.2, 34.6, 46.3,47.3, 85.6, 114.5, 122.3, 126.2, 128.7, 128.9, 133.8, 147.9, 151.6,206.7; IR (KBr): 2960, 1724, 1601, 1495, 1400, 1269, 1120, 930, 829, 692cm⁻¹; HRMS (FAB): Calculated value [C₂₂H₂₇NO₂S]: 369.1763, observedvalue: 369.1760; [α]_(D) ²³ +118.1 (c=0.28, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=22.5min, minor enantiomer tr=19.1 min.

(2S,3S)-2-anilinooxy-3-(4-tert-butylphenylthio)cyclohexanone

¹H NMR (CDCl₃): δ 1.25 (9H, s), 2.02-2.20 (3H, m), 2.28-2.45 (1H, m),2.63 (2H, d, J=4.9 Hz), 3.61-3.75 (1H, m), 4.27 (1H, dd, J=4.6, 10.3Hz), 6.80-6.97 (3H, m), 7.15-7.26 (2H, m), 7.25-7.40 (4H, m), 7.56-7.72(1H, brs); ¹³C NMR (CDCl₃): δ 27.8, 28.9, 31.2, 34.6, 44.9, 46.7, 85.4,114.7, 122.3, 126.2, 128.9, 129.6, 133.3, 147.9, 151.3, 207.0; IR (KBr):2960, 1722, 1600, 1494, 1396, 1269, 1110, 829, 757, 692 cm⁻¹; HRMS(FAB): Calculated value [C₂₂H₂₇NO₂S]: 369.1763, observed value:369.1761; [α]_(D) ²³ +16.5 (c=0.24, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=17.1min, minor enantiomer tr=13.8 min.

Example 18 (Table 5, Entry 6)

Into a DMF solution (8.1 mL) of 4-tert-butylcyclohexanone (2.2 mmol) andproline (0.18 mmol), a DMF solution (2.7 mL) of nitrosobenzene (1.8mmol) is added at 0 deg C. over 32 hr, and the solution is stirred for0.5 hr at the same temperature. A phosphate buffer solution is added tostop the reaction; organic matters are extracted three times with ethylacetate; the organic phase is washed with saline, and dried with Na₂SO₄.After removing the Na₂SO₄ by filtration, the solvent is distilled awayunder reduced pressure. The product is purified by column chromatographyto obtain the α-aminooxy ketone in 62% yield with 99% ee for the majorproduct. Diastereomer ratio is 50:50.

The optical purity was determined by HPLC using a chiral column.

(2R,4R)-2-anilinooxy-4-tert-butylcyclohexanone

¹H NMR (CDCl₃): δ 0.83 (9H, s), 1.31 (1H, dddd, J=13.4, 4.2, 4.2, 4.2Hz), 1.45-1.62 (2H, m), 1.93-2.02 (1H, m), 2.24 (1H, dd, J=13.7, 5.9Hz), 2.30-2.38 (2H, m), 4.30 (1H, dd, J=12.5, 6.0 Hz), 6.78-6.85 (3H,m), 7.13 (2H, t, J=8.2 Hz), 7.76 (1H, s); ¹³C NMR (CDCl₃): δ 27.6, 32.5,33.6, 39.7, 45.9, 85.8, 114.5, 122.0, 128.9, 148.1, 210.2; IR (neat):2960, 2869, 1728, 1602, 1494, 1367, 1097, 742, 692 cm⁻¹; [α]_(D) ²⁰+79.4 (c=0.33, CHCl₃), >99% ee; HRMS (FAB): Calculated value[C₁₆H₂₃NO₂]: 261.1729, observed value: 261.1729.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=10.2min, minor enantiomer tr=11.0 min.

(2R,4S)-2-anilinooxy-4-tert-butylcyclohexanone

¹H NMR (CDCl₃): δ 0.80 (9H, s), 1.40 (1H, dddd, J=13.4, 4.2, 4.2, 4.2Hz), 1.56-1.65 (1H, m), 1.75 (1H, tt, J=12.2, 3.5 Hz), 1.93-2.01 (1H,m), 2.16-2.18 (2H, m), 2.63 (1H, dt, J=13.9, 6.0 Hz), 4.11 (1H, t, J=4.4Hz), 6.82 (2H, d, J=8.2 Hz), 6.85 (1H, t, J=7.3 Hz), 7.06 (1H, s),7.15-7.18 (2H, m); ¹³C NMR (CDCl₃): δ 27.3, 32.2, 32.3, 38.0, 41.3,84.7, 114.9, 122.6, 128.8, 147.8, 211.6; IR (neat): 2960, 2869, 1724,1673, 1602, 1494, 1367, 1083, 748 cm⁻¹; [α]_(D) ¹⁹ −11.8 (c=0.87,CHCl₃), 94% ee; HRMS (FAB): Calculated value [C₁₆H₂₃NO₂]: 261.1729,observed value: 261.1720.

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn (hexane:2-propanol 100:1). 1.0 mL/min; major enantiomer tr=11.1min, minor enantiomer tr=12.5 min.

Example 19 (Table 5, Entry 7)

Into a DMF solution (8.1 mL) of4-(tert-butyldiphenylsiloxy)cyclohexanone (2.2 mmol) and proline (0.18mmol), a DMF solution (2.7 mL) of nitrosobenzene (1.8 mmol) is added at0 deg C. over 32 hr, and the solution is stirred for 0.5 hr at the sametemperature. A phosphate buffer solution is added to stop the reaction;organic matters are extracted three times with ethyl acetate; theorganic phase is washed with saline, and dried with Na₂SO₄. Afterremoving the Na₂SO₄ by filtration, the solvent is distilled away underreduced pressure. The product is purified by column chromatography toobtain the α-aminooxy ketone in 69% yield with 99% ee for the majorproduct. Diastereomer ratio is 67:33.

The optical purity was determined by HPLC using a chiral column.

(2R,4R)-2-anilinooxy-4-(tert-butyldiphenylsiloxy)cyclohexanone

¹H NMR (CDCl₃): δ 0.98 (9H, s), 1.58 (1H, t, J=12.7 Hz), 1.70 (1H,J=12.9 Hz), 1.87-1.96 (1H, m), 2.22-2.32 (2H, m), 2.84 (1H, dt, Jd=6.0,Jt=13.8 Hz), 4.23 (1H, brs), 4.81 (1H, dd, J=12.6, 6.2 Hz), 6.76 (2H, d,J=8.2 Hz), 6.83 (1H, t, J=6.9 Hz), 7.13 (2H, t, J=6.9 Hz), 7.32 (6H, m),7.57 (4H, dd, J=15.4, 7.8 Hz), 7.69 (1H, s); ¹³C NMR (CDCl₃): δ 19.2,27.0, 34.1, 35.7, 39.2, 67.5, 82.4, 114.5, 122.1, 127.8, 128.9, 130.0,133.5, 135.6, 148.1, 209.9; IR (neat): 2956, 2931, 1725, 1602, 1494,1427, 1112, 1076, 821, 701 cm⁻¹; [α]_(D) ¹⁸ +18.2 (c=0.23, CHCl₃), >99%ee; HRMS (FAB): Calculated value [C₂₈H₃₃NO₃Si]: 459.2230, observedvalue: 459.2273.

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=6.6min, minor enantiomer tr=7.3 min.

(2R,4S)-2-anilinooxy-4-(tert-butyldiphenylsiloxy)cyclohexanone

¹H NMR (CDCl₃): δ 1.08 (9H, s), 1.87-1.95 (1H, m), 2.00 (1H, dt, J=12.5,10.7 Hz), 2.04-2.18 (2H, m), 2.28-2.36 (1H, m), 2.42-2.48 (1H, m),4.09-4.18 (2H, m), 6.81 (2H, d, J=7.9 Hz), 6.93 (1H, t, J=7.9 Hz), 7.22(2H, t, J=7.9 Hz), 7.39-7.46 (6H, m), 7.65-7.70 (4H, m), 7.53 (1H, brs);[α]_(D) ¹⁹ +57.8 (c=1.18, CHCl₃), 96% ee; HRMS (FAB): Calculated value[C₂₈H₃₃NO₃Si]: 459.2230, observed value: 459.2263.

The enantiomeric excess was determined by HPLC using a Chiralpak OD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=10.3min, minor enantiomer tr=11.3 min.

The results in the above EXAMPLES are given in the above Table 1 to thefollowing Table 5.

TABLE 2 Yield, ee, No. Ketone Product % % 1

79 >99^(a) 2

77 >99 3

96 >99 4

87 >99 5

55 96 6

45 99 7

45 >99 8

41 >99 9

69 >99 ^(a)catalyst 30 mol %; for the others, catalyst 10 mol %^(c)Amount of catalyst 10 mol %

As can be seen from the above table, when cyclohexanone ordimethylcyclohexanone is used as a ketone, the corresponding α-aminooxyketone derivative was obtained in a high yield with a highenantioselectivity. In addition, even with a ketone having the acetalsite at the 4-position, the corresponding α-aminooxy ketone derivativewas obtained in a high yield with a high enantioselectivity.

TABLE 3

10 0 30 0 10 −20 30 −20 mol % deg C. mol % deg C. mol % deg C. mol % degC. Entry R Yld, % ee, % Yld, % ee, % Yld, % ee, % Yld, % ee, % 1 Me 8198 80 98 quant 98 quant 98 2 Et 64 98 64 98 88 98 87 99 3 n-Pr 55 98 7197 53 97 81 98 4 i-Pr 72 98 77 97 77 99 77 99 5 CH₂Ph 67 98 72 99 <5 7099 6 Ph 20 44 99 <5 62 99

TABLE 4

Time, Yield, Entry Substrate hr % Product 1

38 43

2

26 60

3

24 70

4

29 72

TABLE 5

Time, Yield, Entry Substrate hr % Product 5

13 61

6

32 62

7

32 69

Experiments for Table 6 Example 20 (Table 6, Entry 1)

Cyclohexanone (1.2 mmol) and 4-tert-butyldimethylsiloxy-L-proline (superproline) (0.06 mmol) are dissolved into 1.0 mL of a DMF solution, andinto this solution, a DMF solution (0.5 mL) of nitrosobenzene (0.6 mmol)is dropped over 15 min. After completion of the dropping, the solutionis stirred at room temperature for 30 min. A phosphate buffer solutionis added to stop the reaction; organic matters are extracted with ethylacetate; the organic phase is washed with saline, and dried with Na₂SO₄.After removing the Na₂SO₄ by filtration, the solvent is distilled awayunder reduced pressure. The product is purified by column chromatographyto obtain the α-aminooxy ketone in 76% yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-cyclohexanone

¹H NMR (CDCl₃): δ 1.37-1.75 (3H, m), 1.82-1.95 (2H, m), 4.27 (2H, dd,J=11.6, 6.2 Hz), 6.82 (3H, t, J=8.1 Hz), 7.12 (2H, t, J=7.6 Hz), 7.71(1H, s); ¹³C NMR (CDCl₃): δ 23.6, 27.1, 32.3, 40.7, 86.1, 114.3, 114.8,128.9, 148.0, 209.7; IR (KBr): 3041, 2942, 2865, 1716, 1600, 1494, 1132,1099, 1072, 1027 cm⁻¹; HRMS (FAB): Calculated value [C₁₂H₁₅NO₂]:205.1103, observed value: 205.1080; [α]_(D) ²³ +119 (c=0.84, CHCl₃).

HPLC: Chiralpak AD-H column (hexane:2-propanol 40:1). 1.0 mL/min; majorenantiomer tr=34.3 min, minor enantiomer tr=28.1 min.

Example 21 (Table 6, Entry 2)

4,4-dimethylcyclohexanone (1.2 mmol) and super proline (0.06 mmol) aredissolved into 1.0 mL of a DMF solution, and into this solution, a DMFsolution (0.5 mL) of nitrosobenzene (0.6 mmol) is dropped over 2 hr.After completion of the dropping, the solution is stirred at roomtemperature for 30 min. A phosphate buffer solution is added to stop thereaction; organic matters are extracted with ethyl acetate; the organicphase is washed with saline, and dried with Na₂SO₄. After removing theNa₂SO₄ by filtration, the solvent is distilled away under reducedpressure. The product is purified by column chromatography to obtain theα-aminooxy ketone in 74% yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-4,4-dimethylcyclohexanone

¹H NMR (CDCl₃): δ 0.97 (s, 3H), 1.14 (s, 3H), 1.48-1.59 (3H, m), 4.38(1H, ddd, J=12.7, 6.4, 3.2 Hz), 2.21-2.28 (1H, m), 2.40 (1H, dt, J=14.1,6.5 Hz), 4.38 (1H, dd, J=12.9, 6.4 Hz), 6.79 (2H, d, J=7.8 Hz), 6.81(1H, t, J=8.1 Hz), 7.13 (2H, t, J=8.1 Hz); ¹³C NMR (CDCl₃): δ 24.9,31.3, 31.9, 44.4, 83.2, 114.2, 121.9, 128.8, 148.1, 210.3; IR (KBr):3041, 2956, 2927, 1725, 1602, 1495, 1470, 1076, 740, 692 cm⁻¹; [α]_(D)¹⁹ +85.7 (c=0.33, CHCl₃); HRMS (FAB): Calculated value [C₁₄H₁₉NO₂]:233.1416, observed value: 233.1423.

HPLC: Chiralcel OD-H column (hexane:2-propanol 40:1). 1.0 mL/min; majorenantiomer tr=9.1 min, minor enantiomer tr=12.2 min.

Example 22 (Table 6, Entry 3)

Tetrahydrothiopyran-4-on (1.2 mmol) and super proline (0.06 mmol) aredissolved into 1.0 mL of a DMF solution, and into this solution, a DMFsolution (0.5 mL) of nitrosobenzene (0.6 mmol) is dropped over 2 hr.After completion of the dropping, the solution is stirred at roomtemperature for 30 min. A phosphate buffer solution is added to stop thereaction; organic matters are extracted with ethyl acetate; the organicphase is washed with saline, and dried with Na₂SO₄. After removing theNa₂SO₄ by filtration, the solvent is distilled away under reducedpressure. The product is purified by column chromatography to obtain theα-aminooxy ketone in 68% yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.(R)-3-anilinooxy-tetrahydrothiopyran-4-on ¹H NMR (CDCl₃): δ 2.76-2.95(4H, m), 3.04 (1H, dd, J=11.5, 13.0 Hz), 3.19 (1H, dd, J=5.4, 13.0 Hz),4.63 (1H, dd, J=5.4, 11.5 Hz), 6.90-6.97 (3H, m), 7.22-7.26 (2H, m),7.68 (1H, brs); ¹³C NMR (CDCl₃): δ 30.2, 33.8, 44.9, 86.4, 114.6, 122.4,128.9, 147.8, 206.3; IR (KBr): 3262, 2925, 1724, 1602, 1494, 1469, 1415,1309, 1101, 1076, 993, 783, 692 cm⁻¹; HRMS (FAB): Calculated value[C₁₁H₁₃NO₂S]: 223.0667, observed value: 223.0667; [α]_(D) ²¹ +85.7(c=0.69, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak AS-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=19.9min, minor enantiomer tr=22.6 min.

Example 23 (Table 6, Entry 4)

Cycloheptanone (1.2 mmol) and super proline (0.06 mmol) are dissolvedinto 1.0 mL of a DMF solution, and into this solution, a DMF solution(1.0 mL) of nitrosobenzene (0.6 mmol) is dropped over 2 hr. Aftercompletion of the dropping, the solution is stirred at room temperaturefor 30 min. A phosphate buffer solution is added to stop the reaction;organic matters are extracted with ethyl acetate; the organic phase iswashed with saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain the α-aminooxyketone in 45% yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-cycloheptanone

¹H NMR (CDCl₃): δ 1.32-1.44 (1H, m), 1.59-1.78 (3H, m), 1.79-1.91 (3H,m), 2.05-2.12 (1H, m), 2.41-2.51 (1H, m), 2.52-2.61 (1H, m), 4.60 (1H,dd, J=9.4, 3.9 Hz), 6.87-6.97 (3H, m), 7.20-7.32 (2H, m), 7.53 (1H, bs);¹³C NMR (CDCl₃): δ 23.1, 26.5, 28.6, 30.0, 41.1, 88.2, 114.4, 122.1,128.9, 148.0, 211.6; IR (KBr): 3021, 2979, 2402, 1752, 1603, 1520, 1472,1215, 1026, 930 cm⁻¹; [α]_(D) ²² +59.9 (c=0.61, CHCl₃); HRMS (FAB):Calculated value [C₁₃H₁₇NO₂]: 219.1259, observed value: 219.1235.

The enantiomeric excess was determined by HPLC using a (Chiralcel) AD-Hcolumn (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=20.2min, minor enantiomer tr=16.2 min.

Example 24 (Table 6, Entry 5)

3-pentanone (6 mmol) and super proline (0.06 mmol) are dissolved into1.0 mL of a DMF solution, and into this solution, a DMF solution (1.0mL) of nitrosobenzene (0.6 mmol) is dropped over 1 hr. After completionof the dropping, the solution is stirred at room temperature for 30 min.A phosphate buffer solution is added to stop the reaction; organicmatters are extracted with ethyl acetate; the organic phase is washedwith saline, and dried with Na₂SO₄. After removing the Na₂SO₄ byfiltration, the solvent is distilled away under reduced pressure. Theproduct is purified by column chromatography to obtain the α-aminooxyketone in 50% yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(R)-2-anilinooxy-3-pentanone

¹H NMR (CDCl₃): δ 1.09 (3H, t, J=7.3 Hz), 1.41 (3H, d, J=7.0 Hz), 2.53(2H, q, J=7.3 Hz), 4.45 (1H, q, J=7.0 Hz), 6.89-6.99 (3H, m), 7.21-7.28(2H, m), 7.30 (1H, bs); ¹³C NMR (CDCl₃): δ 7.3, 15.9, 31.5, 84.1, 114.5,122.4, 129.0, 148.0, 211.6; IR (neat): 3278, 2979, 2937, 1718, 1603,1495, 1101, 901, 692 cm⁻¹; [α]_(D) ²³ +75.5 (c=0.29, CHCl₃); HRMS (FAB):Calculated value [C₁₁H₁₅NO₂]: 193.1103, observed value: 193.1097.

The enantiomeric excess was determined by HPLC using a (Chiralcel) OD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=16.5min, minor enantiomer tr=20.6 min.

Example 25 (Table 6, Entry 6)

Into a CH₃CN solution (3.0 mL) of phenylacetoaldehyde (1.8 mmol) andnitrosobenzene (0.6 mmol), super proline (0.06 mmol) is added at 0 degC., and the solution is stirred for 2 hr at the same temperature. i-PrOH(1.0 mL) and NaBH₄ (3 mmol) are added, and stirred for 10 min; then aphosphate buffer solution is added to stop the reaction; organic mattersare extracted with ethyl acetate; the organic phase is washed withsaline, and dried with Na₂SO₄. After removing the Na₂SO₄ by filtration,the solvent is distilled away under reduced pressure. The product ispurified by column chromatography to obtain the α-aminoxy aldehyde in50% yield with 99% ee.

The method for determining the optical purity, and the physical valueswere the same as those in EXAMPLE 13.

Example 26 (Table 6, Entry 7)

Into a CH₃CN solution (3.0 mL) of 3-phenyl-propanal (1.8 mmol) andnitrosobenzene (0.6 mmol), super proline (0.06 mmol) is added at 0 degC., and the solution is stirred for 2 hr at the same temperature. i-PrOH(1.0 mL) and NaBH₄ (3 mmol) are added, and stirred for 10 min; then aphosphate buffer solution is added to stop the reaction; organic mattersare extracted with ethyl acetate; the organic phase is washed withsaline, and dried with Na₂SO₄. After removing the Na₂SO₄ by filtration,the solvent is distilled away under reduced pressure. The product ispurified by column chromatography to obtain the α-aminoxy aldehyde in76% yield with 98% ee.

The method for determining the optical purity, and the physical valueswere the same as those in EXAMPLE 12.

TABLE 6 Super Proline proline Time, yld, ee, Time, yld, ee, EntrySubstrate Product hr % % hr % % 1

5.5 77 >99 0.25 76 >99 2

24 84 >99 2 74 >99 3

24 69 >99 2 68 >99 4

24 <5 nd 2 45 >99 5

24 <5 nd 1 50 >99 6

24 <5 nd 2 50  99 7

24 67 98 2 76  98

Example 27

Cyclohexanone (1.2 mmol) and D-proline (0.06 mmol) are dissolved into2.7 mL of a DMF solution, and the solution is cooled to 0 deg C. Intothis solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) isdropped over 5.5 hr. After completion of the dropping, the solution isstirred at the same temperature for 30 min. A phosphate buffer solutionis added to stop the reaction; organic matters are extracted with ethylacetate; the organic phase is washed with saline, and dried with Na₂SO₄.After removing the Na₂SO₄ by filtration, the solvent is distilled awayunder reduced pressure. The product is purified by column chromatographyto obtain the α-aminooxy ketone in 79% yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(S)-2-anilinooxy-cyclohexanone

¹H NMR (CDCl₃): δ 1.37-1.75 (3H, m), 1.82-1.95 (2H, m), 4.27 (2H, dd,J=11.6, 6.2 Hz), 6.82 (3H, t, J=8.1 Hz), 7.12 (2H, t, J=7.6 Hz), 7.71(1H, s); ¹³C NMR (CDCl₃): δ 23.6, 27.1, 32.3, 40.7, 86.1, 114.3, 114.8,128.9, 148.0, 209.7; IR (KBr): 3041, 2942, 2865, 1716, 1600, 1494, 1132,1099, 1072, 1027 cm⁻¹; HRMS (FAB): Calculated value [C₁₂H₁₅NO₂]:205.1103, observed value: 205.1080; [α]_(D) ²³ −119 (c=0.84, CHCl₃).

The enantiomeric excess was determined by HPLC using a Chiralpak AD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=28.1min, minor enantiomer tr=34.3 min.

Example 28

1,4-cyclohexadione monoethyleneketal (1.2 mmol) and D-proline (0.06mmol) are dissolved into 2.7 mL of a DMF solution, and this solution iscooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) ofnitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion of thedropping, the solution is stirred at the same temperature for 30 min. Aphosphate buffer solution is added to stop the reaction; organic mattersare extracted with ethyl acetate; the organic phase is washed withsaline, and dried with Na₂SO₄. After removing the Na₂SO₄ by filtration,the solvent is distilled away under reduced pressure. The product ispurified by column chromatography to obtain the α-aminooxy ketone in 96%yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(S)-7-anilinooxy-1,4-dioxaspiro[4.5]decane-8-on

¹H NMR (CDCl₃): (1.88-2.04 (2H, m), 2.16 (1H, t, J=12.8 Hz), 2.36-2.46(2H, m), 2.62 (1H, dt, J=14.0, 6.8 Hz), 4.38-4.21 (4H, m), 4.60 (1H, dd,J=12.9, 6.5 Hz), 6.87 (2H, d, J=7.7 Hz), 6.90 (1H, t, J=7.2 Hz), 7.20(2H, t, J=7.2 Hz); 13C NMR (CDCl₃): (34.9, 36.0, 39.7, 64.8, 64.9, 82.7,107.6, 114.5, 122.2, 128.9, 148.0, 208.6; IR (neat): 2960, 2888, 1728,1602, 1494, 1305, 1122, 1052 cm⁻¹; [α]_(D) ¹⁸ −78.7 (c=1.2, CHCl₃); HRMS(FAB): Calculated value [C₁₄H₁₇NO₄]: 263.1158, observed value: 263.1172.

The enantiomeric excess was determined by HPLC using a Chiralcel OD-Hcolumn (hexane:2-propanol 10:1). 0.5 mL/min; major enantiomer tr=29.1min, minor enantiomer tr=26.5 min.

Example 29

4,4-dimethylcyclohexanone (1.2 mmol) and L-proline (0.06 mmol) aredissolved into 2.7 mL of a DMF solution, and this solution is cooled to0 deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene(0.6 mmol) is dropped over 12 hr. After completion of the dropping, thesolution is stirred at the same temperature for 30 min. A phosphatebuffer solution is added to stop the reaction; organic matters areextracted with ethyl acetate; the organic phase is washed with saline,and dried with Na₂SO₄. After removing the Na₂SO₄ by filtration, thesolvent is distilled away under reduced pressure. The product ispurified by column chromatography to obtain the α-aminooxy ketone in 87%yield with ee of >99%.

The optical purity was determined by HPLC using a chiral column.

(S)-2-anilinooxy-4,4-dimethylcyclohexanone

¹H NMR (CDCl₃): δ 0.97 (s, 3H), 1.14 (s, 3H), 1.48-1.59 (3H, m), 4.38(1H, ddd, J=12.7, 6.4, 3.2 Hz), 2.21-2.28 (1H, m), 2.40 (1H, dt, J=14.1,6.5 Hz), 4.38 (1H, dd, J=12.9, 6.4 Hz), 6.79 (2H, d, J=7.8 Hz), 6.81(1H, t, J=8.1 Hz), 7.13 (2H, t, J=8.1 Hz); ¹³C NMR (CDCl₃): δ 24.9,31.3, 31.9, 44.4, 83.2, 114.2, 121.9, 128.8, 148.1, 210.3; IR (KBr):3041, 2956, 2927, 1725, 1602, 1495, 1470, 1076, 740, 692 cm⁻¹; [α]_(D)¹⁹ −85.7 (c=0.33, CHCl₃); HRMS (FAB): Calculated value [C₁₄H₁₉NO₂]:233.1416, observed value: 233.1423.

The enantiomeric excess was determined by HPLC using a Chiralcel OD-Hcolumn (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=12.2min, minor enantiomer tr=9.1 min.

For cyclohexanone, dimethylcyclohexanone, andtetrahydro-4H-thiopyran-4-on, the product was obtained in a period oftime much shorter than that when proline is used. For example, forcyclohexanone, the reaction which took 5.5 hr was completed in 15 min.In addition, cycloheptanone and diethylketone reacted slowly withproline, but by using super proline, the α-aminooxy ketones could besynthesized, although the yield was moderate. Any of the compoundsobtained has an extremely high asymetric yield. Because it is alreadyknown that the compounds obtained can be induced into the α-hydroxyketones with a divalent copper salt, (N. Momiyama, H. Yamamoto, J. Am.Chem. Soc., 2003, 125, 6038.), the present reaction can be applied to amethod for synthesizing an α-hydroxy ketone having a high optical puritythrough the asymmetric catalytic reaction from a ketone.

INDUSTRIAL APPLICABILITY

According to the method of the present invention, the correspondingoptically active α-aminooxy ketone can be obtained from a ketone and anitroso compound in a high yield with a high enantioselectivity, using acatalytic amount of proline and, in turn, the α-hydroxy ketone can beeffectively obtained.

In other words, the method of the present invention is an advantageousmethod which eliminates the need for first converting a ketone into anenolate or an equivalent thereof; allows an α-aminooxy ketone derivativeto be directly obtained from a ketone; allows use of proline which islow-cost and readily available as an optically active substance; andallows an α-aminooxy ketone derivative having a high yield and a highoptical purity to be obtained. When the catalyst is proline, the prolinehas the feature of being inexpensive. In addition, when the catalystused is a proline derivative and, in particular, the above-mentionedsuper proline, the corresponding α-aminooxy ketone can be manufacturedsimply in a short period of time with a high yield and a highenantioselectivity, as compared to proline.

In addition, the α-aminooxy ketone derivatives obtained can be easilyinduced into α-hydroxy ketones with a divalent copper salt (Momiyama etal. (Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc., 2003, 125, 6038)),which are useful as medicines and agricultural chemicals.

1. A manufacturing method for an optically active α-aminooxy ketonederivative expressed by formula (1), wherein a ketone expressed byformula (2) is caused to react with a nitroso compound expressed byformula (3) in the presence of proline or a proline derivative expressedby formula (4):

wherein in formulae (1)-(4), R¹ and R² respectively denote an alkyl,alkenyl or alkynyl group which may have a substituent, and R¹ and R² maybe linked to form a ring; R³ denotes an aryl, heterocyclic, alkyl,alkenyl or alkynyl group which may have a substituent; and A denotes ahydrocien atom, alkoxy group, aryloxy group, acyloxy group or silyloxygroup which may have a substituent, and wherein A in formula (4) is asilyloxy group which may have a substituent.
 2. A manufacturing methodfor an optically active α-aminooxy ketone derivative expressed byformula (1′), wherein a ketone expressed by formula (2) is caused toreact with a nitroso compound expressed by formula (3) in the presenceof proline or a proline derivative expressed by formula (4′):

wherein in formulae (1)-(4), R¹ and R² respectively denote an alkyl,alkenyl or alkynyl group which may have a substituent, and R¹ and R² maybe linked to form a ring; R³ denotes an aryl, heterocyclic, alkyl,alkenyl or alkynyl group which may have a substituent; A denotes ahydrogen atom, alkoxy group, aryloxy group, acyloxy group or silyloxygroup which may have a substituent and wherein A in formula (4′) is asilyloxy group which may have a substituent.